Systems Biology. Edda Klipp, Wolfram Liebermeister, Christoph Wierling, Axel Kowald, Hans Lehrach, and Ralf Herwig. A Textbook

Transcription

1 Edda Klipp, Wolfram Liebermeister, Christoph Wierling, Axel Kowald, Hans Lehrach, and Ralf Herwig Systems Biology A Textbook WILEY- VCH WILEY-VCH Verlag GmbH & Co. KGaA

2 v Contents Preface XVII Part One Introduction to Systems Biology 1 1 Introduction Biology in Time and Space Models and Modeling What is a Model? Purpose and Adequateness of Models Advantages of Computational Modeling Basic Notions for Computational Models Model Scope Model Statements System State Variables, Parameters, and Constants Model Behavior Model Classification Steady States Model Assignment is not Unique Data Integration Standards 12 References 12 2 Modeling of Biochemical Systems Kinetic Modeling of Enzymatic Reactions The Law of Mass Action Reaction Kinetics and Thermodynamics Michaelis Menten Kinetics How to Derive a Rate Equation Parameter Estimation and Linearization of the Michaelis Menten Equation The Michaelis Menten Equation for Reversible Reactions 22 Systems Biology: A Textbook. Edda Klipp, Wolfram Liebermeister, Christoph \Vierling, Axel Kowald, Hans Lehrach, and Ralf Herwig Copyright 2009 WILEYWCH Verlag GmbH & Co. KGaA, Weinheim ISBN:

3 VI Contents Regulation of Enzyme Activity by Effectors Substrate Inhibition Binding of Ligands to Proteins Positive Homotropic Cooperativity and the Hill Equation The Monod Wyman Changeux Model for Sigrnoid Kinetics Generalized Mass Action Kinetics Approximate Kinetic Formats Convenience Kinetics Structural Analysis of Biochemical Systems Systems Equations Information Encoded in the Stoichiometric Matrix N Elementary Flux Modes and Extreme Pathways Flux Cone Conservation Relations: Null Space of NT Kinetic Models of Biochemical Systems Describing Dynamics with ODEs Notations Linearization of Autonomous Systems Solution of Linear ODE Systems Stability of Steady States Global Stability of Steady States Limit Cydes Metabolic Control Analysis The Coefficients of Control Analysis The Elastidty Coefficients Control Coefficients Response Coefficients Matrix Representation of the Coefficients The Theorems of Metabolic Control Theory The Summation Theorems The Connectivity Theorems Derivation of Matrix Expressions for Control Coefficients Tools and Data Formats for Modeling Simulation Techniques Petri Nets Cellular Automata Simulation Tools CellDesigner COPASI PyBioS Data Formats Systems Biology Markup Language BioPAX Systems Biology Graphical Notation 73

4 Contents I VII Standards for Systems Biology Data Resources Pathway Databases Databases of Kinetic Data Model Databases 77 References 79 3 Specific Biochemical Systems Metabolic Systems Basic Elements of Metabolic Modeling Toy Model of Upper Glycolysis Threonine Synthesis Pathway Model Signaling Pathways Introduction Function and Structure of Intra- and Intercellular Communication Receptor Ligand Interactions Structural Components of Signaling Pathways G proteins Small G proteins Phosphorelay Systems MAP Kinase Cascades Jak/Stat Pathways Signaling Dynamic and Regulatory Features Quantitative Measures for Properties of Signaling Pathways Crosstalk in Signaling Pathways The Cell Cyde Steps in the Cyde Minimal Cascade Model of a Mitotic Oscillator Models of Budding Yeast Cell Cyde Modeling Nudeo/Cytoplasmatic Compartmentalization Spatial Models Types of Spatial Models Compartment Models and Partial Differential Equations Stochastic Models Cellular Automata Compartment Models Reaction Diffusion Systems The Diffusion Equation Solutions of -the Diffusion Equation Reaction Diffusion Equation Pattern Formation in Tissue Development Spontaneous Pattern Formation Apoptosis Molecular Biology of Apoptosis 132

5 VIII I Contents Modeling of Apoptosis 135 References Model Fitting Data for Small Metabolic and Signaling Systems Databases for Kinetic Modeling Measuring Promoter Activities Using GFP Reporter Genes Parameter Estimation Regression Estimators Method of Least Squares and Maximum-Likelihood Estimation Identifiability Bootstrapping Crossvalidation Bayesian Parameter Estimation Local and Global Optimization Local Optimization Global Optimization Sampling Methods Genetic Algorithms Reduction and Coupling of Models Model Simplification Tacit Model Assumptions Reduction of Fast Processes Response Time Time-Scale Separation Global Model Reduction Linearized Biochemical Models Linear Relaxation Modes Coupled Systems and Emergent Behavior Modeling of Coupled Systems Bottom-Up and Top-Down Modeling Modeling the System Boundary Coupling of Submodels Model Merging Model Selection What is a Good Model? Statistical Tests and Model Selection Maximum-Likelihood Estimation and x 2-Test Overfitting Likelihood Ratio Test Selection Criteria Bayesian Model Selection Cycle of Experiments and Modeling 186

6 Contents 11X Models are Growing in Complexity 186 References Analysis of High-Throughput Data High-Throughput Experiments DNA Array Platforms Platform Comparison Next Generation Sequencing Image Analysis and Data Quality Control Grid Finding Spot Quantification Signal Validity Preprocessing Global Measures Linear Models Nonlinear and Spatial Effects Other Approaches Analysis of Gene Expression Data Planning and Designing Experiments for Case-Control Studies Tests for Differential Expression DNA Arrays Next Generation Sequencing Multiple Testing ROC Curve Analysis Clustering Algorithms Hierarchical Clustering Self-Organizing Maps (SOMs) K-Means Cluster Validation Overrepresentation and Enrichment Analyses Classification Methods Support Vector Machines Other Approaches 229 References Gene Expression Models Mechanisms of Gene Expression Regulation Transcription-Factor Initiated Gene Regulation General Promoter Structure Prediction and Analysis of Promoter Elements Sequence-Based Analysis Approaches that Incorporate Additional Information Posttranscriptional Regulation Through micrornas Identification of micrornas in the Genome Sequence MicroRNA Target Prediction 246

7 XI Contents Experimental Implications RNA Interference 246 Gene Regulation Functions 248 The Lac Operon in Escherichia coli 249 Gene Regulation Functions Derived from Equilibrium Binding 250 Occupation Probability Derived from Statistical Thermodynamics 251 Gene Regulation Function of the Lac Operon 253 Transcriptional Regulation in Larger Networks 254 Network Component Analysis 254 Dynamic Models of Gene Regulation 256 One Gene Regulatory Network: Different Approaches 256 Representation of a Gene Regulatory Network as Graph 256 Bayesian Networks 258 Boolean Networks 259 Description with Ordinary Differential Equations 262 Gene Expression Modeling with Stochastic Processes 264 References Stochastic Systems and Variability Stochastic Modeling of Biochemical Reactions Chemical Random Process for Molecule Numbers The Chemical Master Equation Stochastic Simulation Direct Method Explicit r-leaping Method Stochastic Simulation and Spatial Models The Chemical Langevin Equation Deterministic and Stochastic Modeling Frameworks Temporal Fluctuations Fluctuations in Gene Expression Stochastic Model of Transcription and Translation Macroscopic Kinetic Model Microscopic Stochastic Model Fluctuations and Protein Bursts Measuring the Intrinsic and Extrinsic Variability Temporal Fluctuations in a Gene Cascade Linear Model of Two Genes Measuring the Time Correlations in Protein Levels Biological Functions of Noise Random Switching Exploration Strategies Variability and Uncertainty Models with Uncertain Constant Parameters Computing the Distribution of Output Variables Monte Carlo Simulation 293

8 Approximation for Narrow Parameter Distributions Temporal Parameter Fluctuations Uncertainty Analysis of Biochemical Models Sampling of Reaction Elasticities Distributions for Kinetic Parameters Principle of Minimal Information Thermodynamic Constraints an Parameters Obtaining Parameter Distributions from Experimental Data Robustness Robustness Properties in Biochemical Systems Biological Robustness Properties Mathematical Robustness Criteria Precise Robustness in a Bacterial Two-Component System Structural Robustness in Large Networks Backup Genes Backup Pathways Quantitative Robustness by Feedback Negative Feedback Integral Feedback Scaling Laws, Invariance, and Dimensional Analysis Summation Laws and Homogeneous Functions Summation Theorems Conservation Laws for Sensitivity Compensation of Correlated Fluctuations Robustness and Evolvability Robustness and Modeling 310 References Network Structures, Dynamics, and Function Structure of Biochemical Networks Mathematical Graphs Random Graphs Erdios R6nyi Random Graphs Geometric Random Graphs Random Graphs with Predefined Degree Sequence Scale-Free Networks Clustering and Local Structure Clustering Coefficient Small-World Networks Network Motifs Structure of Metabolic Networks The Network Picture Network Motifs Transcription Networks and Network Motifs Single Regulation Arrows and Their Steady-State Response 328 Contents 1X1

9 XIII Contents Adaptation Motif 329 Negative Feedback 330 Feed-Forward Loops 331 Dynamic Model of the Feed-Forward Loop 332 Dynamics and Function of Network Motifs 333 Modularity 335 Modularity as a Fact or as an Assumption 336 Aspects of Modularity: Structure, Function, Dynamics, Regulation, and Genetics 337 Structural Modules in Cellular Networks 337 Modular Response Analysis 338 Functional Modules Detected by Epistasis 339 Evolution of Modularity and Complexity 341 Tinkering and Engineering 341 Analogy in Evolution 342 Modularity, Robustness, and Evolvability 342 References Optimality and Evolution Optimality and Constraint-Based Models Optimization by Evolution Optimality Studies in Systems Biology The Fitness Function Optimality and Compromise Cost-Benefit Calculations Inequality Constraints Local Optima Constraint-Based Flux Optimization Flux-Balance Analysis Geometrie Interpretation of Flux-Balance Analysis Thermodynamic Constraints Applications and Tests of Flux-Optimization Paradigm Optimal Enzyme Concentrations Optimization of Catalytic Properties of Single Enzymes Optimal Distribution of Enzyme Concentrations in a Metabolic Pathway Temporal Transcription Programs Evolutionary Garne Theory Game Theory Hawk Dove Game and Prisoner's Dilemma Best Choices and Nash Equilibrium Evolutionary Garne Theory Replicator Equation for Population Dynamics The Replicator Equation Outcomes of Frequency-Dependent Selection 372

10 Contents 1X Evolutionary Stable Strategies Dynamical Behavior in the Rock-Scissors-Paper Game Evolution of Cooperative Behavior Kin Selection Other Scenarios for Evolution of Cooperation Yield and Efficiency in Metabolism Trade-off Between Fast and Efficient Energy Metabolism Multicellularity Enables Cells to Profit from Respiration 377 References Cell Biology Introduction The Origin of Life Molecular Biology of the Cell Chemical Bonds and Forces Important in Biological Molecules Functional Groups in Biological Molecules Major Classes of Biological Molecules Carbohydrates Lipids Proteins Nucleic Acids Structural Cell Biology Structure and Function of Biological Membranes Nudeus Cytosol Mitochondria Endoplasmatic Reticulum and Golgi Complex Other Organelles Expression of Genes Transcription Processing of the mrna Translation Protein Sorting and Posttranslational Modifications Regulation of Gene Expression 416 References Experimental Techniques in Molecular Biology Introduction Restriction Enzymes and Gel Electrophoresis Cloning Vectors and DNA Libraries D and 2D Protein Gels Hybridization and Blotting Techniques Southern Blotting Northern Blotting Western Blotting 429

11 XIV I Contents In Situ Hybridization 430 Further Protein Separation Techniques 430 Centrifugation 430 Column Chromatography 431 Polymerase Chain Reaction 432 DNA and Protein Chips 433 DNA Chips 433 Protein Chips 434 Yeast Two-Hybrid System 434 Mass Spectrometry 435 Transgenic Animals 436 RNA Interference 437 ChIP an Chip and ChIP-PET 439 Surface Plasmon Resonance 441 Population Heterogeneity and Single Entity Experiments 442 References Mathematics Linear Modeling Linear Equations The Gaussian Elimination Algorithm Systematic Solution of Linear Systems Matrices Basic Notions Linear Dependency Basic Matrix Operations Dimension and Rank Eigenvalues and Eigenvectors of a Square Matrix Ordinary Differential Equations Notions Regarding Differential Equations Linearization of Autonomous Systems Solution of Linear ODE Systems Stability of Steady States Global Stability of Steady States Limit Cydes Difference Equations Graph and Network Theory Linear Networks Boolean Networks Bayesian Networks 473 References Statistics Basic Concepts of Probability Theory Random Variables, Densities, and Distribution Functions 478

12 Contents 1XV Transforming Probability Densities Product Experiments and Independence Limit Theorems Descriptive Statistics Statistics for Sample Location Statistics for Sample Variability Density Estimation Correlation of Samples Testing Statistical Hypotheses Statistical Framework Two Sample Location Tests Linear Models ANOVA Multiple Linear Regression Principal Component Analysis 496 References Stochastic Processes Basic Notions for Random Processes Reduced and Conditional Distributions Markov Processes Markov Chains Jump Processes in Continuous Time: The Master Equation Continuous Random Processes Langevin Equations The Fokker Planck Equation 509 References Control of Linear Systems Linear Dynamical Systems System Response Random Fluctuations and Spectral Density The Gramian Matrices Databases Databases of the National Center for Biotechnology Databases of the European Bioinformatics Institute EMBL Nucleotide Sequence Database Ensembl InterPro Swiss-Prot, TrEMBL, and UniProt Protein Databank BioNumbers Gene Ontology Pathway Databases 524

13 XVII Contents ConsensusPathDB 524 References Modeling Tools Introduction Mathematica and Matlab Mathematica Example Matlab Example Dizzy Systems Biology Workbench Tools Compendium 536 References 551 Index 553